The goal of this project is the development of therapeutic agents for diseases that can be treated by inhibiting zinc hydrolytic enzymes, including rheumatoid and osteoarthritis, periodontitis, glaucoma, and cancer. The design of these agents requires a knowledge of (1) the mechanism of the enzyme and (2) the energies of binding interactions between the enzyme and an inhibitor. It is difficult to measure the contribution of an individual type of interaction in an enzyme due to its size and complexity. This proposal focuses on two zinc hydrolytic enzymes, carbonic anhydrase and carboxypeptidase A. It is believed that many other zinc enzymes are similar in structure and utilize similar mechanisms. Our approach to these problems is to design, synthesize, and study small molecule models of the enzymes to test mechanistic hypotheses for use for in drug design. The synthesis of the compounds requires characterization by various methods, including low and high resolution EI- and FAB-MS.